Xmrv the puppet master and the master switch>

How about correlation with people that either lose weight and those that gain weight during the course of the disease? I mean if the switch is off, no energy is produced, fat is stored for later use, if the switch is on but it overdrive, stored fats are being used up and the person loses weight... does that make sense?

Click to expand...

I've been sick 24 years and have always been thin until I got sick. My weight gain may be due to the fact I'm in a wheelchair and get very little excercise. It was either use a wheelchair or be bedridden for all these years. My thyroid has been a problem too.

" Hildreth explained that NPC is likely disrupting HIV transmission by affecting the trafficking of the viral protein Gag. "The very dramatic thing in NPC cells is the Gag protein seems to never make it to the plasma membrane."

Recently, James Hildreth at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV, suggesting these cells would not spread the virus.

These findings, published May 27 in the Journal of Virology, are rooted in a hypothesis Hildreth has explored for a long time: that "cholesterol is somehow essential" to HIV, he said. For instance, HIV-1 relies on specialized structures known as lipid rafts, which are rich in cholesterol, to infect new cells.

Click to expand...

I,m referring to the ability of retroviruses to use base sequences within these genes in the formation of these rafts and their ability to "sail" between membranes of organelles before integrating with the DNA of the host making exposure to the cytoplasm absolutely minimal.The rafts can be intracellular or intercellular.In cell cell they transfer via fusion with the cell membranes and the membranes of the internal organelles such as rough and smooth endoplasmic reticulem golgi apparatus etc .A real stealth bomber

Always been on the thin side. Had some teenage plumpness which I progressively started losing after marriage at 18. Don't know if it is marriage responsibilities or body maturity that started my weight loss, or abnormalities that later became CFS.

After diagnosis, I started FFC treatment and lost down to 93 pounds. I am 5'4".

I am back up to 98 now. But I did get concerned there for a while. What what point is my weight loss a problem? Doctor told me to drink Boost three times a day. I did once or twice. That stuff is expensive.

While I was losing weight, I was feeling better.

Now, I am not on the strong FFC treatment. I don't know what it was they were giving me. Of course, it could also have been the disease that caused the weight loss. I will never know.

I,m referring to the ability of retroviruses to use base sequences within these genes in the formation of these rafts and their ability to "sail" between membranes of organelles before integrating with the DNA of the host making exposure to the cytoplasm absolutely minimal.The rafts can be intracellular or intercellular.In cell cell they transfer via fusion with the cell membranes and the membranes of the internal organelles such as rough and smooth endoplasmic reticulem golgi apparatus etc .A real stealth bomber

Click to expand...

Hi Gerwyn, I am trying to learn as much as possible about how retroviruses associate with lipid rafts so therefore your explanation was very helpful..thank you !

Could the XMRV Env protein also associate with lipid rafts by being palmitoylated ?

eg " These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association."

Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

To investigate the association of the murine leukemia virus (MuLV) Env protein with lipid rafts, we compared wild-type and palmitoylation-deficient mutant Env proteins by using extraction with the mild detergent Triton X-100 (TX-100) followed by a sucrose gradient flotation assay. We found that the wild-type MuLV Env protein was resistant to ice-cold TX-100 treatment and floated to the top of the gradients. In contrast, we observed that the palmitoylation-deficient mutant Env protein was mostly soluble when extracted by ice-cold TX-100 and stayed at the bottom of the gradients. Both the wild-type and mutant Env proteins were found to be soluble when treated with methyl-beta-cyclodextrin before extraction with ice-cold TX-100 or when treated with ice-cold octyl-beta-glucoside instead of TX-100. These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association. Although the palmitoylation-deficient Env mutant was synthesized at a level similar to that of the wild-type Env, it was found to be expressed at reduced levels on the cell surface. We observed syncytium formation activity with both the wild-type and mutant Env proteins, indicating that palmitoylation or raft association is not required for MuLV viral fusion activity.
PMID: 12414927 [PubMed - indexed for MEDLINE]

Abstract
In a previous study we showed that budding of HIV-1 particles occurs at highly specialized membrane microdomains known as lipid rafts. These microdomains are characterized by a distinct lipid composition that includes high concentrations of cholesterol, sphingolipids, and glycolipids. Since cholesterol is known to play a key role in the entry of some other viruses, our observation of HIV budding from lipid rafts led us to investigate the role in HIV-1 entry of cholesterol and lipid rafts in the plasma membrane of susceptible cells. We have used 2-OH-propyl-beta-cyclodextrin (beta-cyclodextrin) to deplete cellular cholesterol and disperse lipid rafts. Our results show that removal of cellular cholesterol rendered primary cells and cell lines highly resistant to HIV-1-mediated syncytium formation and to infection by both CXCR4- and CCR5-specific viruses. beta-Cyclodextrin treatment of cells partially reduced HIV-1 binding, while rendering chemokine receptors highly sensitive to antibody-mediated internalization...

Hi Gerwyn, I am trying to learn as much as possible about how retroviruses associate with lipid rafts so therefore your explanation was very helpful..thank you !

Could the XMRV Env protein also associate with lipid rafts by being palmitoylated ?

XMRV is a MuLV class virus the env gene has a very similar base sequence.raft formation is controlled by base sequences within the gag and pol genes which are virtually identical in xmrv compared with Mulv apart from a higher degree of deletions downsream of the alternative start codon.As deletions dont code for anything I would say yes.
eg " These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association."

Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

To investigate the association of the murine leukemia virus (MuLV) Env protein with lipid rafts, we compared wild-type and palmitoylation-deficient mutant Env proteins by using extraction with the mild detergent Triton X-100 (TX-100) followed by a sucrose gradient flotation assay. We found that the wild-type MuLV Env protein was resistant to ice-cold TX-100 treatment and floated to the top of the gradients. In contrast, we observed that the palmitoylation-deficient mutant Env protein was mostly soluble when extracted by ice-cold TX-100 and stayed at the bottom of the gradients. Both the wild-type and mutant Env proteins were found to be soluble when treated with methyl-beta-cyclodextrin before extraction with ice-cold TX-100 or when treated with ice-cold octyl-beta-glucoside instead of TX-100. These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association. Although the palmitoylation-deficient Env mutant was synthesized at a level similar to that of the wild-type Env, it was found to be expressed at reduced levels on the cell surface. We observed syncytium formation activity with both the wild-type and mutant Env proteins, indicating that palmitoylation or raft association is not required for MuLV viral fusion activity.
PMID: 12414927 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9871-5.

Click to expand...

XMRV is a MuLV class virus the env gene has a very similar base sequence.raft formation is controlled by base sequences within the gag and pol genes which are virtually identical in xmrv compared with Mulv apart from a higher degree of deletions downsream of the alternative start codon.As deletions dont code for anything I would say yes.
eg " These results indicate that the MuLV Env protein is associated with lipid rafts and that palmitoylation of the Env protein is critical for lipid raft association."

I've been sick 24 years and have always been thin until I got sick. My weight gain may be due to the fact I'm in a wheelchair and get very little excercise. It was either use a wheelchair or be bedridden for all these years. My thyroid has been a problem too.

Click to expand...

Despite having a low fat diet before getting ill, after developing ME a cholestrol test showed high levels, Dr Myhill said it wasn't my diet but a thyroid problem. I had high CMV levels and lately EBV levels showed an active infection. I too have put weight on, like you little exercise is not good but we have no choice.

Chris Hempel said
Quote " I am wondering if XMRV utilizes cholesterol and lipid rafts to do its dirty work and whether the Niemann Pick Type C gene could help the XMRV virus assemble in the body like it does with HIV-AIDS? "

" Since receiving the devastating news that our girls have Niemann Pick Type C disease, we have appeared on TV shows like The Doctors and DATELINE to educate people on the disease and explain what its like to deal with two 5 year old kids with dementia. The good news is that some people do listen. Dr. Judy Mikovitz of the Whittemore Petersen Institute in Reno, Nevada (where I live) heard of my complaints of a viral illness striking our family in 2005. She offered to do some testing. At first nothing turned up, but I remained persistent in trying to get to the bottom of what was going on.

Annette, I hope you are doing well. I am so sorry I have not been in touch but I have been swamped with working with our doctors and the FDA to treat the girls with cyclodextrin. Last year, Judy ran some special testing on Addi and Cassi. I know that whatever she tested turned out negative but I am wondering what she was looking at. Did she look at NKT cells by chance (see attached)? Something is going on with the girls immune systems and I am trying to get to the bottom of it. The HIV/AIDS researcher I am working with thinks that there is something going on with transcription factors and t-cells.

Chris, last year we looked at inflammatory cytokines and chemokines and the Rnase L activity. The cytokines and chemokines were within the normal adult ranges (though we know nothing about ranges in small children). The RNase L activity was high but that is consistent with active infection (EBV?). We only had 6 mls of blood so we could not do the panel of immune cells NK and NKT or the important T cell component. We would like to do these studies and now that we have the LSR (18 color flow cytometer up and running) we could do an in depth immune profiling. I would also like to look at the girls immune system in light of a recent new discovery made here at the WPI (but not yet public knowledge). If possible could we get ~15 mls from the girls this week? We have a window of opportunity before the holiday and vacations and would be delighted to do all the testing here at the WPI lab that you visited last year Applied Research facility Rm 401 on Evans. We can also pick up the blood at your convenience.

I provided Dr. Mikovits with additional blood samples from the twins. Sure enough Addi and Cassi tested positive for an active infection of XMRV. One twin (Cassi) tested with more severity. Cassi is the same twin that had more severe symptoms at the onset of contracting the virus. There must be something here to research further.

Interestingly, for the past year and a half I have been working with a leading HIV-AIDS researcher who discovered that the HIV-AIDS virus (also a retro virus like XMRV) uses cholesterol and the Niemann Pick Type C gene to do its dirty work in the human body. I am wondering if XMRV utilizes cholesterol and lipid rafts to do its dirty work and whether the Niemann Pick Type C gene could help the XMRV virus assemble in the body like it does with HIV-AIDS? "

Mitochondrial dysfunction and subsequent ATP deficiency which is induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC disease,
so by reducing the level of cholesterol within mitochondrial membranes using methyl--cyclodextrin they are actually restoring the activity of ATP synthase.

Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl--cyclodextrin can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.

I would assume then that mutated NPC1 therefore results in a severe defect in oxidative phosphorylation [OXPHOS]
This ATP synthase defect in NPC1 would result in a significantly decreased ATP synthase in the brain and there would also be a significant loss of ATP levels in the brain, I also would assume that cholesterol levels in lipid rafts in the brain would perhaps be decreased ?
Does anyone else agree with this ?

Has anyone looked at ways to improve OXPHOS or supplements to use to improve oxidative phosphorylation function ?
How would you increase ATP levels ? how do you restore ATP synthase function ?
Any ideas would be appreciated ..please

I've recently discovered that the athletic performance supplement, creatine, boosts my ATP levels enough to make a difference in both energy and brain functioning. If you check out Dr. Myhill's theory on mitochondrial dysfunction in CFS it says something like: used ATP converts to ADP which does not get recycled back to ATP (as it should), instead it converts to AMP which can only be recycled back to ATP via the use of caffeine (which has always helped with me with energy, but increases vaso contriction, which unfortunately adds to brain fog). I've experimented with creatine at various levels for a few months with some success. By taking 5 grams of creatine, and some additional supplements that help the body remove lactic acid, before exercising, I've managed to bypass (70-80%) of P.E.M. I did this while attempting anaerobic exercise (weight training) at level I wouldn't normally attempt. My creatine trial and error continues to be a work-in-progress, and is part of a larger protocol which includes methylation supplements (recommended by RichV, Yasko, Myhill, etc.) along with other sups, most of which have been discussed on this board. As an fyi, I've had moderate to severe CFS for twenty years.

Many Thanks for sharing this information ,
I have read some good reports about creatine supplementation, some of the research says that creatine helps to maintain and build muscle mass and it can provide more energy and it is also used in certain neuromuscular degenerative diseases.
I am glad to hear that it is working for you and it sounds like you are doing very well, I like the idea of combining creatine with other supplements
Best Wishes for a continual improvement in your health !

Until relatively recently, dogma had it that mitochondria do not
contain cholesterol. Now we know that mitochondrial
membranes both contain this lipid and that the organelle
metabolizes it. The work of Yu et al below shows that the
amount of cholesterol is significantly elevated within
mitochondrial membranes of Niemann Pick Disease C1 type
(NPC1) mouse brain and neurons Also, there is a decreased
ATP synthase activity and reduced mitochondrial membrane
potential. Reducing the level of cholesterol with the drug
methyl-SS-cyclodextrin restored ATP synthase activity.
The authors argue that ATP deficiency induced by altered
cholesterol metabolism in mitochondria explains the neuronal
impairment in NPC1 disease.

Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl--cyclodextri n can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.